Substituted bicyclic compounds as bromodomain inhibitors

Abstract

The invention relates to substituted bicyclic compounds, which are useful for inhibition of BET protein function by binding to bromodomains, pharmaceutical compositions comprising these compounds, and use of the compounds and compositions in therapy.

What is claimed is: 
     
       1. A compound of formula: 
       
         
           
           
               
               
           
         
         or a tautomer, pharmaceutically acceptable salt, or hydrate thereof, 
         wherein: 
         D 1  is selected from isoxazole and pyrazole, optionally substituted with one or more groups independently selected from deuterium, alkyl(C 1 -C 4 ), alkoxy(C 1 -C 4 ), amino, halogen, amide, —C(O)cycloamino, —CF 3 , CN, —N 3 , ketone (C 1 -C 4 ), —S(O)Alkyl(C 1 -C 4 ), —SO 2 alkyl(C 1 -C 4 ), -thioalkyl(C 1 -C 4 ), —COOH and ester,
 wherein said alkyl(C 1 -C 4 ), alkoxy(C 1 -C 4 ), amino, amide, ketone (C 1 -C 4 ), —S(O)Alkyl(C 1 -C 4 ), —SO 2 alkyl(C 1 -C 4 ), -thioalkyl(C 1 -C 4 ), and ester are optionally substituted with one or more groups independently selected from hydrogen, F, Cl, Br, —OH, —NH 2 , —NHMe, —OMe, —SMe, oxo, and thio-oxo; 
 
         X is present and selected from —(NH)—, —O—, —NHCR x R y —, —NHSO 2 —, and —CR x R y NH—; 
         Z 1  is —NR a ; 
         R a  is selected from hydrogen, deuterium, and alkyl (C 1-3 ); 
         R 3  is selected from isoxazole, pyrazole, pyridyl, thiazole, isothiazole, pyrimidine, phenyl, cyclohexene, benzo[d]oxazolyl, naphthyl, and quinolyl, optionally substituted with one or more groups independently selected from deuterium, alkyl(C 1 -C 4 ), —OH, alkoxy(C 1 -C 4 ), amino, halogen, amide, —CF 3 , ON, —N 3 , ketone (C 1 -C 4 ), —S(O)Alkyl(C 1 -C 4 ), —SO 2 alkyl(C 1 -C 4 ), -thioalkyl(C 1 -C 4 ), carboxyl, and ester,
 wherein said alkyl(C 1 -C 4 ), alkoxy(C 1 -C 4 ), amino, amide, ketone (C 1 -C 4 ), —S(O)Alkyl(C 1 -C 4 ), —SO 2 alkyl(C 1 -C 4 ), -thioalkyl(C 1 -C 4 ), and ester are optionally substituted with one or more group independently selected from hydrogen, F, Cl, Br, —OH, —NH 2 , —NHMe, —OMe, —SMe, oxo, and/or thio-oxo; 
 
         R 1  and R 2  are independently selected from hydrogen, deuterium, alkyl, —OH, —NH 2 , -thioalkyl, and alkoxy; and 
         R x  and R y  are each independently selected from hydrogen, alkyl(C 1-5 ), halogen, —OH, —CF 3 , deuterium, amino, and alkoxy(C 1-5 ), or two substituents selected from R x , R y  and R 1  may be connected in a 5- or 6-membered ring to form a bicyclic carbocycle or bicyclic heterocycle. 
       
     
     
       2. The compound of  claim 1 , wherein D 1  is 
       
         
           
           
               
               
           
         
       
     
     
       3. A compound of formula: 
       
         
           
           
               
               
           
         
         or a tautomer, pharmaceutically acceptable salt, or hydrate thereof, 
         wherein: 
         D 1  is selected from isoxazole and pyrazole, optionally substituted with one or more groups independently selected from deuterium, alkyl(C 1 -C 4 ), alkoxy(C 1 -C 4 ), amino, halogen, amide, —C(O)cycloamino, —CF 3 , CN, —N 3 , ketone (C 1 -C 4 ), —S(O)Alkyl(C 1 -C 4 ), —SO 2 alkyl(C 1 -C 4 ), -thioalkyl(C 1 -C 4 ), —COOH, and ester,
 wherein said alkyl(C 1 -C 4 ), alkoxy(C 1 -C 4 ), amino, amide, ketone (C 1 -C 4 ), —S(O)Alkyl(C 1 -C 4 ), —SO 2 alkyl(C 1 -C 4 ), -thioalkyl(C 1 -C 4 ), and ester are optionally substituted with one or more groups independently selected from hydrogen, F, Cl, Sr, —OH, —NH 2 , —NHMe, —OMe, —SMe, oxo, and thio-oxo; 
 
         X is optionally present, and if present, is selected from —(NH)—, —O—, —NHCR x R y —, —NHSO 2 —, and —CR x R y NH—; 
         Z 1  is —NR a ; 
         R a  is selected from hydrogen, deuterium, and alkyl (C 1 -C 3 ); 
         R 3  is selected from isoxazole, pyrazole, pyridyl, thiazole, isothiazole, pyrimidine, phenyl, cyclohexene, benzo[d]oxazolyl, naphthyl, and quinolyl, optionally substituted with one or more groups independently selected from deuterium, alkyl(C 1 -C 4 ), —OH, alkoxy(C 1 -C 4 ), amino, halogen, amide, —CF 3 , ON, —N 3 , ketone (C 1 -C 4 ), —S(O)Alkyl(C 1 -C 4 ), —SO 2 alkyl(C 1 -C 4 ), -thioalkyl(C 1 -C 4 ), carboxyl, and ester,
 wherein said alkyl(C 1 -C 4 ), alkoxy(C 1 -C 4 ), amino, amide, ketone (C 1 -C 4 ), —S(O)Alkyl(C 1 -C 4 ), —SO 2 alkyl(C 1 -C 4 ), -thioalkyl(C 1 -C 4 ), and ester are optionally substituted with one or more groups independently selected from hydrogen, F, Cl, Br, —OH, —NH 2 , —NHMe, —OMe, —SMe, oxo, and thio-oxo; 
 
         R 1  and R 2  are independently selected from hydrogen, deuterium, alkyl, —OH, —NH 2 , -thioalkyl, and alkoxy; and 
         R x  and R y  are each independently selected from hydrogen, alkyl(C 1-5 ), halogen, —OH, —CF 3 , deuterium, amino, and alkoxy(C 1-5 ), or two substituents selected from R x , R y  and R 1  may be connected in a 5- or 6-membered ring to form a bicyclic carbocycle or bicyclic heterocycle. 
       
     
     
       4. The compound of  claim 3 , wherein D is 
       
         
           
           
               
               
           
         
       
     
     
       5. A compound selected from:
 4,6-bis(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one; 
 5,7-bis(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(2-methylpyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(4-methylpyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-one; 
 7-(1,3-dimethyl-1H-pyrazol-4-yl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(2-(trifluoromethyl)pyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(4-methylisothiazol-5-yl benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-7-(4-fluoro-2-(trifluoromethyl)phenyl)-1-methyl-1 benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-7-(2-methoxy-5-methylphenyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-7-(2-methoxypyridin-yl)-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 3-(6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2-methylbenzonitrile; 
 4,6-bis(3,5-dimethylisoxazol-4-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one; 
 3-(6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-4-methylbenzonitrile; 
 5-(3,5-dimethylisoxazol-4-yl)-7-(4-methoxypyridin-3-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-7-(5-fluoro-2-methoxyphenyl)-1-methyl-1-benzo[d]imidazol-2(3H)-one; 
 7-(5-chloro-2-methylphenyl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 7-(6-amino-2-methylpyridin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 7-(3,5-dimethyl-1H-pyrazol-4-yl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 6-(3,5-dimethylisoxazol-4-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one; 
 6-(5-dimethylisoxazol-4-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole-2(3H)-thione; 
 6-(3,5-dimethylisoxazol-4-yl)-4-(4-methylpyridin-3-yl)-1H-benzo[d]imidazole-2-thiol; 
 3-(6-(3,5-dimethylisoxazol-4-yl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-4-methylbenzonitrile; 
 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-((1,3,5-trimethyl-1H-pyrazol-4-yl)amino)-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-((2-methylpyridin-3-yl-amino)-1H-benzo[d]imidazol-2(3H)-one; 
 5-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-1-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one; 
 3-(6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-4-methylbenzamide; 
 3-(6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4H yl)-2-methylbenzamide; 
 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-((2-methylpyridin-3-yl)oxy)-1H-benzo[d]imidazol-2(3H)-one; 
 7-(3,5-dimethyl-1H-pyrazol-4-yl)-5-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-7-(3,5-dimethylisoxazol-4-yl)amino)-1-methy H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(naphthalen-1-yl)-1H-benzo[d]imidazol-2(3H)-one; 
 7-(3,5-dichloropyridin-4-yl)-5-(3,5-dimethylisoxazol-4-yl)-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(3-methylpyridin-4-yl)-1H-benzo[d]imidazol-2(3H)-one; 
 7-(2-chlorophenyl)-5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(3-methylpyridin-4-yl)-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-7-(3,5-dimethylpyridin-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(o-tolyl)-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-7-(2-fluoro-5-methoxyphenyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 7-(5-chloro-2-methoxyphenyl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-7-(2-fluoro-3-methoxyphenyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-7-(2,4-dimethylthiazol-5-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 5-(3,5-dimethylisoxazol-4-yl)-7-(2-methoxy-6-methylpyridin-3-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 7-(benzo[d]oxazol-5-yl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; 
 7-(cyclohex-1-en-1-yl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; and 
 tautomers, pharmaceutically acceptable salts, and hydrates thereof. 
 
     
     
       6. A pharmaceutical composition comprising a compound of  claim 5 , or a tautomer, pharmaceutically acceptable salt, or hydrate thereof, and a pharmaceutically acceptable carrier.